Ethanol use can be an important source of morbidity and mortality worldwide. It is known that half of individuals with significant burn injuries necessitating hospitalization were positive for ethanol. More importantly, ethanol use at the time of injury also results in increased morbidity and mortality in the burned patients. Validated murine models combining ethanol + thermal burn injury have demonstrated a massive acute systemic effect of these combined agents involving lung, small intestine and liver. A delayed effect of combining ethanol + thermal burn injury is systemic immunosuppression. Though not associated with the same morbidity/mortality as thermal burn injuries, ethanol use has also been demonstrated to be a risk factor for UV-mediated sunburns. The mechanisms by which ethanol augments the effects of these environmental epidermal injuries are unknown. This proposal is a renewal of a long-standing grant that has served to characterize the role of the lipid mediator platelet-activating factor (PAF) in skin pathophysiology. Exerting its effects via a specific G-protein coupled receptor (PAF-R) widely expressed, acute PAF exposure results in a systemic pro-inflammatory response and delayed immunosuppression. Thus, PAF biosynthesis and degradation are tightly regulated. Our previous studies have demonstrated that environmental stressors including UV radiation mediate their acute and delayed effects via PAF. Our ongoing studies have discovered that acute exposure of keratinocytes in vitro or mice in vivo with ethanol followed by thermal burn injury or UVB results in a tremendous increase in PAF production. Moreover, pilot studies combining acute ethanol exposure along with UVB irradiation or burn injury resulted in systemic inflammation in wild-type but not in PAF-R deficien (Ptafr-/-) mice. Three aims are designed to test the hypothesis that acute ethanol exposure bypasses the tightly regulated PAF synthetic pathways resulting in exaggerated PAF production in response to thermal burn or UVB injuries, and that PAF mediates the acute pro-inflammatory and delayed immunosuppressive responses to combined ethanol and burn/UVB injury. The first aim will use wild-type and Ptafr-/- mice to define the role of the PAF system in the acute multisystem organ injury and delayed immunosuppressive effects of combining ethanol + thermal burn/UVB skin injury. Mice lacking the PAF metabolizing enzyme PAF- acetylhydrolase will be used to define if this enzyme can modify effects of ethanol + environmental injury. The second aim will define the exact mechanism how ethanol augments PAF biosynthesis in keratinocytes by assaying PAF synthetic and metabolizing pathways. The third aim will test if localized UVB treatment of human subjects exposed to ethanol results in increased PAF production and exaggerated skin responses. These studies will provide clinically important information which will result in a better understanding and new therapeutic approaches for environmental injuries in the setting of acute ethanol exposure.